1. Field of the Invention
The present invention relates to improved interpretation of noisy physiologic and biochemical signals by the use of filtering, prediction and trend analysis of patient data, and discloses a method and device and/or a computer program product that aims at improving motivation, self-control and self-management of patients having type 2-diabetes or diabetes-related disease. The invention monitors oxygen utilisation of the heart, thus physical condition and fitness, and indicates stimulants and drug abuse and psychological and emotional stress. The invention discloses the use of a painless, non-invasive surrogate measure for blood glucose, as well as blood glucose prediction by sparse blood sampling, and a metabolic performance indicator. The invention offers long-term, metabolic monitoring at low cost combined with ease of use, and creates patient awareness of metabolic system function relating to the disease in an intuitive way, needing very little effort by the user. Lower cost, a lower burden for the health care system, prolonged lifespan and increased quality of life for the patient may be gained from the use of the proposed invention.
2. Description of Prior Art
Physiologic and biochemical signals for example blood glucose sampling, blood pressure and other monitored signals of mammalians can be very noisy, having a high variance when sampled over time. It is therefore critical to reduce such noise before accurate interpretation of the data can be made. Further, biochemical signals are often invasive in nature and such measurements can be discomfortable, costly or complicated to apply. The proposed invention strives to improve accuracy in interpretation of such signals by the use of suitable filtering methods and to reduce discomfort and cost by the use of non-invasive surrogate measures.
Diabetes is increasing globally in epidemic proportions and stands for a massive cost burden of healthcare. Type 1-diabetes, stands for around 10% of all diabetes cases. Type 2-diabetes, therefore stands for around 90% of all diabetes cases, and is steadily increasing. In the United States alone, it is estimated that up to 7% of the population may have diabetes. 100 million individuals are overweight, thus at high risk for type 2-diabetes. If this trend continues, 100% of the US adult population will be obese in year 2030. Total yearly cost of diabetes in the US including indirect costs where 1997 estimated to approximate USD 100 billion. In Saudi Arabia it has been estimated that up to 25% of the population may have diabetes related disease. The World Health Organization (WHO) predicts an increase to 300 million diabetes patients worldwide by the year 2025. Various attempts have been made to reverse this global epidemic trend, but to date this has failed.
Type 1-diabetes, (earlier referred to as insulin dependent diabetes mellitus IDDM), is identified by irreversible beta-cell destruction, that usually results in absolute insulin deficiency. Type 2-diabetes, (earlier referred to as non-insulin dependent diabetes mellitus, NIDDM), is identified as a heterogeneous disorder believed to involve both genetic and environmental factors. Type 2-diabetes is to a great extent a lifestyle related disease where modern sedentary lifestyle in combination with poor eating habits is believed to be major sources of the problem. The type 2-diabetes patient typically does not require insulin treatment for survival. The typical symptoms of type 2-diabetes are: Thirst, frequent urination, drowsiness, fatigue, overweight, gustatory sweating, varying blurred vision, elevated blood sugar levels, acetone breath and sugar in the urine. An examination of the patient will quite typically reveal a sedentary lifestyle and a distinct preference for a diet high in saturated fats and refined carbohydrates.
Insulin resistance is a common metabolic abnormality that characterizes individuals with various medical disorders including type 2-diabetes and obesity and occurs in association with many cardiovascular and metabolic abnormalities. Insulin resistance is defined as the inability of the body to respond adequately to insulin. The Syndrome-X or Metabolic Syndrome, also named the Insulin Resistance Syndrome, is a cluster of metabolic and physiologic risk factors that predict the development of type 2-diabetes and related cardiovascular diseases. It is generally characterized by five major abnormalities; obesity, hypertension, insulin resistance, glucose intolerance and dyslipedaemia. The prevalence rate of the metabolic syndrome in western countries is 25-35%. Aging is generally associated with insulin resistance and deteriorating beta cell function and obesity with insulin resistance and hyperinsulinemia.
Diabetic autonomic neuropathy (DAN) is a serious and one of the most common complications of diabetes. Most type 2-diabetes patients die in cardiovascular diseases preceded by a deterioration of the functionality of the autonomic nervous system (ANS). This is seldom noticed at an early stage, making type 2-diabetes a “stealth” disease developing slowly over the years and is most often unnoticed by the patient until discovered at a late stage. DAN impairs the ability to conduct normal activities of daily living, lowers quality of life, and increases the risk of death. DAN affects many organ systems throughout the body e.g., gastrointestinal, genitourinary, and cardiovascular. DAN is a result of nerve fibre destruction and loss related to the “toxic” effects of elevated blood glucose levels. Intensive glycaemic control is therefore critical in preventing the onset and slowing the progression of DAN. ANS problems and DAN can successfully be detected by the assessment of heart rate variability (HRV) analysis.
Hypertension is a major health problem in the western population and associated to cardiovascular disease. Arterial stiffening may be both a cause and consequence of hypertension, however recent research suggests that arterial stiffening is the typical precursor to hypertension, and that arterial stiffening is likely to have a genetic basis. The majority of type 2-diabetes patients (over 50%) suffer from hypertension. It is therefore imperative to control the blood pressure of diabetic patients. In type 2-diabetes it is recommended to keep the blood pressure below 130/80 either by improving life-style or by medication or a combination of both.
Insulin resistance and type 2-diabetes are associated with changes in plasma lipoprotein levels. Up to 70% of patients with type 2-diabetes have lipid disorders. Coronary heart disease is the leading cause of death among patients with type 2-diabetes. Dyslipidemia, together with obesity, hypertension, and hyperglycemia contribute strongly to coronary heart disease. Even mild degrees of dyslipidemia may elevate coronary heart disease risk factors. As these risk factors are additive or even multiplicative, strategies for lifestyle improvement should not only focus on hyperglycemia but also on dyslipidemia. As dyslipidemia in type 2-diabetes usually show smaller and denser LDL-particles, which are more atherogenic, the target for cholesterol lowering should include very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) as well as lowering of elevated triglycerides (TG).
Mental stress, elevated blood-pressure and elevated heart rate are common problems of today's society. Modern work and lifestyle is less physically active where hi-tech related jobs often result in a sedentary lifestyle. High demand work with sustained high levels of stress is common and a negative effort/reward factor can contribute to stress induced disease. It is well known that mental stress can influence metabolism such as elevated blood-glucose levels as well as an increased systolic blood pressure and heart rate. Various stimulants such as caffeine, nicotine, alcohol, cocaine and amphetamine also increase systolic blood pressure and heart rate.
Modern type of diet, high in energy and fat content is associated with insulin resistance and related disorders. The exact aetiology of insulin resistance is however not clear. Genetic predisposition and environmental factors including quality and quantity of dietary fat, both contribute to development of an inability to adequately dispose plasma glucose at normal plasma insulin levels. Fast food outlets are gaining popularity due to high sugar, fat-rich and tasty food in combination with time-efficient eating. The increased consumption of fast-acting, high-energy carbon hydrates reflects in blood sugar overshoots and insulin overshoots followed by blood sugar undershoots and drowsiness, again demanding renewed intake of fast-acting carbon hydrates etc. This cyclic feedback is frequently pounding the metabolic regulatory system. Such transient excitation is believed in the long term to be harmful and contribute to insulin resistance and elevated insulin levels, the early start-up of the type 2-diabetes process. The above life-style related problems are currently creating health problems of a magnitude unheard of in the past.
Physical activity, thus aerobic fitness is the cornerstone in fighting type 2-diabetes related disease. It is a most important task to improve cardiovascular fitness by physical activity that increases the capability and efficiency of the heart to supply the cardiovascular system with oxygen as well as improve insulin sensitivity and oxygen uptake of the muscles. The heart functions like any muscle that it can be trained to become stronger and more efficient. A weight reduction by only 10% usually shows positive effects on blood glucose and lipid levels. In particular, it is important to reduce abdominal fat mass.
Physical activity and energy expenditure can be estimated in a variety of ways that do not constrain the patient during his normal daily activities. Different methods exist like pedometers, accelerometers, heart-rate meters etc. One popular method use a pedometer to calculate number of steps walked or approximate the calories so consumed by a simple formula. Others calculate energy expenditure in relation to body movement and acceleration by the use of single-axial, bi-axial or tri-axial accelerometers. Another method use pulse monitoring based on plethysmograps, (a device that shines light through a finger or earlobe to calculate heart rate and physical activity). One other popular device, a pulse watch, measures the EKG signal by the use of a chest-strap with electrodes and transmits the EKG pulses to a specially designed wrist-watch calculator, which can calculate calories consumed and other parameters related to physical activity. However the simplest way to quantify physical activity is to just roughly estimate the daily activity, for example on a scale from one to five, relating to the daily effort made and the intensity and duration of the physical activity performed. More elaborate calculation and reporting methods include the MET tables (metabolic equivalent) or formula, which is an accurate index of the intensity of physical activity. Modern inactive and sedentary lifestyle has opened up a large market for health gymnasiums and marketing of various health-related products, and physical training programs for the improvement of physical fitness. Despite this positive trend, type 2-diabetes related disease is rapidly increasing at an alarming rate.
It is difficult to motivate high-risk, overweight, sedentary and diabetes-prone individuals to change life style. Just informing the individual of the health-risks involved and the need of physical training and/or the need for corrected eating habits and/or de-stressing treatment is often not sufficient. Low fit individuals often do not feel comfortable by being examined by somebody else or being forced to exercise training in gymnasiums. It is common to find overweight individuals embarrassed by their low physical fitness level, and in order to avoid humiliation, refuse to join rehabilitation programmes. It is believed by the inventor that the only way to break such detrimental trend is to educate people by hands-on experience by the use of simple and intuitive tools to monitor their own metabolic function, preferably at home in private. The individual can then himself gain understanding of the problems involved and gain insight to what extent and intensity it is necessary to change lifestyle.
Self monitoring using a personal blood-glucose meter is usually necessary for type 1 insulin dependent diabetes mellitus (IDDM) patients in order to aid self-administration of insulin. However it is less common that blood-glucose monitoring is prescribed for patients with manifest or borderline type 2-diabetes. Self-monitoring using urine dipsticks for urine-glucose measurements are more or less obsolete today and seldom used due to the fact that the renal threshold varies individually over a wide range. In addition this method cannot measure glucose levels below the renal threshold, exhibits long delay and low sensitivity, and therefore the use of blood-glucose monitoring is preferred.
Recent research has reported some benefits of using a blood-glucose meter for BG-monitoring in connection with meals for patients with type 2-diabetes. The idea is to monitor pre-prandial and post-prandial glucose levels to gain knowledge of the metabolic effect of the meal on the patient. The patient can then learn by experience how the glucose level will raise post-prandially and give him feedback on the glucose variation relating to different types of food intake. The idea is to balance the food intake, where a reduction in refined fast acting carbohydrates will reduce post-prandial blood-glucose overshoots. Such overshoots are understood to cause long-term damage to the autonomic nervous system and eventually may lead to diabetes and diabetic neuropathy. Such form of self-monitoring is cumbersome and impractical to maintain and it is not uncommon that patients drop out of such test trials due to lack of motivation relating to the intensity of the method. Blood glucose meters and tools need to be carried around by the patient during the day and testing is sometimes disclosed in public when having a meal in a restaurant. Including such cumbersome procedures as part of a patient's long-term daily practice is not very likely to succeed. In addition the cost is not negligible according to the consumption of a number of blood-glucose sticks and a number of finger-puncturing lances during the day. In addition, although such test is minimally invasive in nature it can be painful and very uncomfortable to the patient. Further it gives little room for logic and intuitive interpretation of the results and it is therefore difficult to comprehend and administer for the patient in order to obtain a therapeutic goal, a serious disadvantage.
The World Health Organisation (WHO) and American Diabetes Association (ADA) has specified blood-glucose ranges and levels in order to differentiate between the different stages of diabetes. Fasting glucose concentrations that diagnose the symptomatic patient (WHO criteria, 1999) are shown below. Fasting sample glucose concentrations are in mmol/L:
Whole BloodPlasmaVenousCapillaryVenousCapillaryManifest Diabetes Mellitus>6.1>6.1>7.0>7.0Impaired glucose tolerance<6.1<6.1<7.0<7.0(IGT)Impaired fasting glucose5.6-6.05.6-6.06.1-6.96.1-6.9(IFG)Normal<5.5<5.5<6.0<6.0
When assessing blood-glucose levels in the clinic, it is unfortunately quite common to overlook the existence of a strong biologic variability as well as an analytic variability. Thus substantial variability exists between observations that may be misinterpreted by the inexperienced physician resulting in reduced accuracy in grading and diagnosis of the disease.
When a blood sample is drawn in a clinic, a number of factors influence the accuracy of the measurement result such as:                1. Sub-optimum calibration of the clinical analysis instrument. See a practical example in FIG. 1.        2. Aging of the blood sample by glycolysis, as glucose preservatives does not totally prevent glycolysis.        3. “White-Coat Hyperglycemia”, elevated BG value due to a nervous “needle-phobia” patient. See a practical example in FIG. 2.        4. A continuously falling fasting BG value, related to increasing time of day.        5. A time-variable insulin sensitivity, thus different sensitivity from day to day.        6. Female cyclic hormonal changes due to menstruation.        7. BG can vary due to transitory acute infections, traumatic stress and even a simple cold or flu.        
Relating to the above uncertainties, it is believed by the inventor that blood-glucose monitoring under controlled conditions in the home, using a sufficiently accurate blood-glucose meter together with suitable post-processing and filtering methods, improves the accuracy of the diagnostic classification. This is believed by the inventor, to be superior compared to established clinical laboratory measurements and current praxis.
Although elevated insulin levels (hyperinsulinemia) appears in the bloodstream long before elevated blood glucose levels eventually manifest; yet a high glucose level remains the classic type 2-diabetes symptom classifier. Insulin levels are rarely, if ever, used as a diabetic risk marker or diagnostic tool except for clinical research purposes, a remarkable fact. Thus, a low blood glucose level does not preclude the presence of the disease.
Monitoring of oxygen saturation is common practice of patients under emergency treatments as well as in the operating theatre. Before the invention of the now widely used pulse-oximeter, (an instrument that monitors blood haemoglobin oxygen saturation using infrared light absorption), it was common practice to calculate the Rate-Pressure-Product (RPP) of the patient during surgery to establish the patients heart condition and oxygen utilization. The RPP (also called the Double Product) is a reasonably accurate measure of heart oxygen utilization and is derived by multiplying the systolic blood pressure by the heart rate (RPP=sBP×HR/100). After the introduction of the pulse oximeter, RPP has found little use today, but has some use in sports medicine indicating oxygen consumption of the heart during treadmill exercise tests etc. RPP also indicate stress and the use of stimulating drugs.
In order to ease the burden for the patient, the inventor declares that only fasting blood glucose sampling is necessary for accurate long term monitoring and treatment of type 2-diabetes related disease. Even sparsely sampled blood glucose measurements for example once a week may be sufficient, relating to an embodiment of the invention for an accurate prediction of daily BG. More intensive and cumbersome blood glucose monitoring like pre- and postprandial blood glucose measurements during the day is not deemed necessary as the fasting blood glucose level generally indicates the relative magnitude of postprandial blood glucose excursions. Thus a higher fasting blood glucose level is reflected in a higher postprandial blood glucose level and vice versa. This can be indicated by the use of multiple three-sample oral glucose tolerance OGTT tests sampled at 0 h, 1 h and 2 h during an intervention lifestyle improvement period see FIG. 3. It can be seen that as life-style is improved with lower fasting BG, also the postprandial BG-values follows the declining trend. However, 1 h post-prandial BG measurements may of course be used as an alternative to fasting BG when deemed necessary. This is however more cumbersome and therefore less practical as explained above.
In an additional embodiment of the invention, the BG level is predicted from preferably blood pressure and heart rate (Rate Pressure Product) alone, making painful finger pricking or painful invasive procedures unnecessary except for the initial calibration and set-up procedure of the predictor. In another embodiment of the invention, it offers less frequent need of painful finger pricking.
The proposed invention offers the patient an intuitive way to measure and analyse certain physiologic parameters such as for example intensity of physical activity, blood-glucose, blood pressure and heart rate. In addition important patient data such as lipid levels, total cholesterol, triglycerides, body temperature, weight, body mass index and the waist to hip ratio can be stored and processed. Following such measurements, data is processed and optimised using suitable filtering algorithms, and thereafter indicated to the patient in an intuitive manner for instant feedback of his behaviour, progress and results.
A preferred embodiment of the invention comprises the following steps:
Estimating or measuring the level of physical activity on a preferably daily basis, and preferably collecting this information into a database.
Measuring the fasting and/or post-prandial blood-glucose level on a more or less frequent basis, densely or sparsely sampled, and preferably collecting this information into a database.
Measuring the systolic-diastolic and heart rate on a frequent basis, densely sampled, and preferably collecting this information into a database
Calculate the rate pressure product from systolic blood pressure and heart rate.
Measure any other relevant physiological parameter such as body weight, body temperature, blood lipids etc and preferably collecting this information into a database
Low-pass filter, enhance, error-correct and missing data-interpolate the above data using statistical and/or signal processing methods.
Apply prediction methods to predict blood glucose values from preferably the rate pressure product.
Combine and/or filter obtained data by suitable algorithms to noise-reduce, clarify and improve the so obtained information for presentation.
Present the processed, enhanced and/or predicted data as a trend to the patient in an intuitive and easy to understand manner for easy interpretation of patient parameters.
From the above, it becomes clear that metabolic monitoring of diabetes related disease is essential in order to assess at least the current status of a subject. Dense sampling of vital biological parameters offers several advantages. The main advantage is that the subject is continuously made aware of his current status so his health condition does not deteriorate. An other advantage is that the subject continuously receives an overview over any changes or trends in his current status, which may for example relate to a lack of physical activity or a lack of good nutrition in the worse case, or sufficient physical activity and a well-controlled diet in the better case. Yet another important advantage is that the subject gets instantaneous feedback of his status and can adjust his lifestyle according to the developing trend. The prerequisite for efficient metabolic monitoring according to the invention is that the subject monitors vital biologic parameters. For example blood glucose levels, blood pressure and heart rate can be measured at wake-up in the morning and physical activity can be measured during the day etc.
Accurate blood glucose monitoring requires invasive measurements, although finger pricking may be considered as minimally invasive. Currently there is no other method that can compare in accuracy to an invasive measurement. A subject pricks his finger to sample a small amount of blood, which is subsequently examined in an analytical device, which outputs a blood glucose value. Even minimally invasive methods are costly, and often experienced as discomfortable and can thus have a negative impact on the patient and disease management.